dCubilin- or dAMN-mediated protein reabsorption in Drosophila nephrocytes modulates longevity.

Aging is a multi-faceted process regulated by multiple cellular pathways, including the proteostasis network. Pharmacological or genetic enhancement of the intracellular proteostasis network extends lifespan and prevents age-related diseases. However, how proteostasis is regulated in different tissues throughout the aging process remains unclear. Here, we show that Drosophila homologs for Cubulin/Amnionless (dCubilin/dAMN)-mediated protein reabsorption from hemolymph (fly equivalent of blood) by nephrocytes modulates longevity through regulating proteostasis in muscle and brain tissues in Drosophila. We find that overexpression of dAMN receptor in nephrocytes extends lifespan, whereas nephrocyte-specific dCubilin or dAMN RNAi knockdown results in a protein reabsorption defect and shortens lifespan in flies. And we show that dCubilin/dAMN-mediated protein reabsorption in nephrocytes regulates proteostasis in hemolymph and improves healthspan. In addition, we show that enhanced dCubilin/dAMN-mediated protein reabsorption in nephrocytes slows down the aging process in muscle and brain by maintaining the proteostasis network in these tissues. Furthermore, our study shows that dCubilin/dAMN -mediated protein reabsorption in nephrocytes affects proteasome activity in the whole body and muscle tissues. Altogether, our work has revealed an inter-organ communication network across nephrocytes and muscle/neuronal tissue which is essential to maintain proteostasis and to delay senescence in these organs. The findings have provided insights into the role of renal protein reabsorption in the aging process via this tele-proteostasis network.